It is estimated that about one third of the world's population has been exposed to tuberculosis. It is not known how many of these individuals harbor live bacilli in a form of latent tuberculosis, but it may be a significant percentage. Exactly why tuberculosis takes a chronic/latent form in many people is not understood, nor is it clear what conditions [other than immune deficiency] can cause the disease to reactivate from latent to active infection. The purpose of this proposal is to use mouse and guinea pig animal models to attempt to understand these events more clearly. Following aerosol exposure to low doses of Mycobacterium tuberculosis both animal species initially develop a chronic disease state in which the bacterial load remains essentially constant. In some strains of mice this state persists for the lifespan of the animal, during which several definable stages were seen in which cell populations increased and then declined within the granuloma, and were replaced by an increasingly fibrotic response. Moreover, in certain susceptible inbred mouse strains and in guinea pigs the disease reactivates after a period of time. Together, these data seem to imply that the granulomatous response in the lungs is a continuing dynamic event, and is probably driven not by truly latent bacteria, but by bacteria trying periodically to reactivate. Accordingly, we propose to study these events over the course of the disease using a battery of histology, immuno-histochemistry, and immunological techniques. We will study the kinetics of influx and apparent loss of cell populations in the lung granuloma, the expression of cytokine, chemokine, and blood vessel adhesion molecules, and the phenotype, cytokine profile, and antigen recognition of incoming T cells. As a result, we should be able to formulate a picture of how the granuloma is built, and why it gradually degenerates. In addition we will test our working hypothesis that mice that rely more heavily on innate rather than acquired immunity in the lungs are much more prone to reactivation disease, as well as a hypothesis regarding the detection of these events in the guinea pig model by skin testing. Finally, a third component of this grant application will look at the infecting bacilli directly, by studying potential changes in bacterial structure induced in adaptation to changes now understood to exist in the phagosomal environment. In this latter endeavor we shall be assisted by highly qualified mycobacterial chemists from within the Mycobacteria Research Laboratories [MRL] at CSU.